Skip to main content
Log in

Latent Autoimmune Diabetes in Adults (LADA)

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

References

  1. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20:1183–1197.

    Google Scholar 

  2. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus: provisional report of a WHO consultation. Diabet Med 1998;15:539–553.

    Google Scholar 

  3. Naik RG, Palmer JP. Late-onset type 1 diabetes. Current Opin Endocrinol Diabetes 1997;4:308–315.

    Google Scholar 

  4. Kuzuya T, Matsuda A. Classification of diabetes on the basis of etiologies versus degree of insulin deficiency. Diabetes Care 1997;20:219–220.

    Google Scholar 

  5. Service EJ, Rizza RA, Zimmerman BR, Dyck PJ, C OBP, Melton LJ. The classification of diabetes by clinical and C-peptide criteria: A prospective population-based study. Diabetes Care 1997;20:198– 201.

    Google Scholar 

  6. Van der Auwera B, Van Waeyenberge C, Schuit F, Heimberg H, Vandewalle C, Gorus F, Flament J. DRB1*0403 protects against IDDM in Caucasians with the high-risk heterozygous DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 genotype. Belgian Diabetes Registry. Diabetes 1995;44:527–530.

    Google Scholar 

  7. Neifing JL, Greenbaum CJ, Kahn SE, McCulloch DK, Barmeier H, Lernmark A, Palmer JP. Prospective evaluation of ß-cell function in insulin autoantibody-positive relatives of insulin-dependent diabetic patients. Metabolism 1993;42:482–486.

    Google Scholar 

  8. McCulloch DK, Palmer JP. The appropriate use of B-cell function testing in the preclinical period of type 1 diabetes. Diabet Med 1991;8:800–804.

    Google Scholar 

  9. Pihoker C, Brooks-Worrell BM, Greenbaum CJ, Palmer PJ. Impact of islet reactive T cells and autoantibodies on clinical diagnosis of type 1, type 2, or a typical diabetes in children. Diabetes 2000;49(S1):A409-(Abstr).

    Google Scholar 

  10. Libman I, Pietropaolo M, Arslanian S, Laporte R, Becker D. Risk factors associated with type 2 diabetes in youngsters with type 1a (autoimmune) diabetes: Does it matter? Diabetes 2001;50(S2):A39-(Abstr).

    Google Scholar 

  11. Hathout EH, Thomas W, Shahawy MEL, Nahab F, Mace JW. Diabetic autoimmune markers in children and adolescents with type 2 diabetes. Pediatrics 2001:1–4.

  12. Juneja R, Palmer JP. Type 1 12 diabetes: Myth or reality. Autoimmunity 1999;29:65–83.

    Google Scholar 

  13. Karjalainen J, Salmela P, Ilonen J, Surcel HM, Knip M. A comparison of childhood and adult type I diabetes mellitus. N Engl J Med 1989;320:881–886.

    Google Scholar 

  14. Lorenzen T, Pociot F, Hougaard P, Nerup J. Long-term risk of IDDM in first-degree relatives of patients with IDDM. Diabetologia 1994;37:321–327.

    Google Scholar 

  15. Gleichmann H, Zorcher B, Greulich B, Gries FA, Henrichs HR, Betrams J, Kolb H. Correlation of islet cell antibodies and HLADR phenotypes with diabetes mellitus in adults. Diabetologia 1984;27:90–92.

    Google Scholar 

  16. Hagopian WA, Karlsen AE, Gottsater A, Landin Olsson M, Grubin CE, Sundkvist G, Petersen JS, Boel E, Dyrberg T, Lernmark A. Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64K autoantibody positivity at onset predicts diabetes type. J Clin Invest 1993;91:368–374.

    Google Scholar 

  17. Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 1993;42:359–362.

    Google Scholar 

  18. Kobayashi T, Tamemoto K, Nakanishi K, Kato N, Okubo M, Kajio H, Sugimoto T, Murase T, Kosaka K. Immunogenetic and clinical characterization of slowly progressive IDDM. Diabetes Care 1993;16:780–788.

    Google Scholar 

  19. Leslie RD, Pozzilli P. Type I diabetes masquerading as type II diabetes. Possible implications for prevention and treatment. Diabetes Care 1994;17:1214–1219.

    Google Scholar 

  20. Anonymous. Insulin-dependent? Lancet 1985;2:809–810.

    Google Scholar 

  21. Borg H, Gottsäter A, Landin-Olsson M, Fernlund P, Sundkvist G. High levels of antigen-specific islet antibodies predict future betacell failure in patients with onset of diabetes in adult age. J Clin Endocrinol Metab 2001;86:3032–3038.

    Google Scholar 

  22. Urakami T, Miyamoto Y, Matsunaga H, Owada M, Kitagawa T. Serial changes in the prevalence of islet cell antibodies and islet cell antibody titer in children with IDDM of abrupt or slow onset. Diabetes Care 1995;18:1095–1099.

    Google Scholar 

  23. Zimmet PZ. The pathogenesis and prevention of diabetes in adults: Genes autoimmunity, and demography. Diabetes Care 1994;18:1050–1064.

    Google Scholar 

  24. Yeung V, Chan JCN, Chow CC, Zimmet P, Cockrum CS. Antibodies to glutamic acid decarboxylase (anti-GAD) in Chinese IDDM patients. 15th International Diabetes Federation Congress Proceedings, Kobe, Japan, 1994.

  25. Nakanishi K, Kobayashi T, Miyashita H, Okubo M, Sugimoto T, Murase T, Kosaka K, Hara M. Relationships among residual β-cells, exocrine pancreas, and islet-cell antibodies in insulin-dependent diabetes mellitus. Metabolism 1993;42:196–203.

    Google Scholar 

  26. Juneja R, Hirsch IB, Naik RG, Brooks-Worrell BM, Greenbaum CJ, Palmer JP. Islet cell antibodies and glutamic acid decarboxylase antibodies but not the clinical phenotype help to identify type 1 12 diabetes in patients presenting with type 2 diabetes. Metabolism 2001;50:1008–1013.

    Google Scholar 

  27. Palmer JP, Hirsch IB. What's in a name: Latent autoimmune diabetes of adults, type 1.5, adult-onset, and type 1 diabetes. Diabetes Care 2003;26:536–538.

    Google Scholar 

  28. Gottsater A, Landin Olsson M, Fernlund P, Lernmark A, Sundkvist G. β-cell function in relation to islet cell antibodies during the first 3 yr after clinical diagnosis of diabetes in type II diabetic patients. Diabetes Care 1993;16:902–910.

    Google Scholar 

  29. Martino GV, Tappaz ML, Braghi S, Dozio N, Canal N, Pozza G, Bottazzo GF, Grimaldi LM, Bosi E. Autoantibodies to glutamic acid decarboxylase (GAD) detected by an immuno-trapping enzyme activity assay: Relation to insulin-dependent diabetes mellitus and islet cell antibodies. J Autoimmun 1991;4:915–923.

    Google Scholar 

  30. Verge CF, Gianani R, Kawasaki E, Yu LP, Pietropaolo F, Chase HP, Eisenbarth GS. Number of autoantibodies (against insulin, GAD or ICA512/IA2) rather than particular autoantibody specificities determines risk of type I diabetes. J Autoimmun 1996;9:379–383.

    Google Scholar 

  31. Verge CF, Gianani R, Kawasaki E, Yu LP, Pietropaolo M, Jackson RA, Chase HP, Eisenbarth GS. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 1996;45:926–933.

    Google Scholar 

  32. Rowley MJ, Mackay IR, Chen QY, Knowles WJ, Zimmet PZ. Antibodies to glutamic acid decarboxylase discriminate major types of diabetes mellitus. Diabetes 1992;41:548–551.

    Google Scholar 

  33. Palmer JP. What is the best way to predict IDDM? Lancet 1994;343:1377–1378.

    Google Scholar 

  34. Park Y, Lee HK, Koh CS, Min HK, Rowley M, Mackay IR, Zimmet P, Mcarthy B, McCanlies E, Dorman J, Trucco M. The low prevalence of immunogenetic markers in Korean adult-onset IDDM patients. Diabetes Care 1996;19:241–245.

    Google Scholar 

  35. Imagawa A, Hanafusa T, Miyagawa J, Matsuzawa Y, for the Osaka IDDM Study Group. A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. N Engl J Med 2000;342:301–307.

    Google Scholar 

  36. Lernmark A. Rapid onset type 1 diabetes with pancreatic exocrine dysfunction. N Engl J Med 2000;342:344–345.

    Google Scholar 

  37. Borg H, Marcus C, Sjoblad S, Fernlund P, Sundkvist G. Islet cell antibody frequency differs from that of glutamic acid decarboxylase antibodies/IA2 antibodies after diagnosis of diabetes. Acta Paediatr 2000;89:46–51.

    Google Scholar 

  38. Borg H, Gottsäter A, Fernlund P, Sundkvist G. A 12-year prospective study of the relationship between islet antibodies and β-cell function at and after the diagnosis in patients with adult-onset diabetes. Diabetes 2002;51:1754–1762.

    Google Scholar 

  39. Seissler J, De Sonnaville JJJ, Morgenthaler NG, Steinbrenner H, Glawe D, Khoo-Morgenthaler UY, Lan MS, Notkins AL, Heine RJ, Scherbaum WA. Immunological heterogeneity in type 1 diabetes: Presence of distinct autoantibody patterns in patients with acute onset and slowly progressive disease. Diabetologia 1998;41:891– 897.

    Google Scholar 

  40. Hampe CS, Kockum I, Landin-Olsson M, Törn C, Örtqvist E, Persson O, Rolandsson O, Palmer JP, Lernmark Å. GAD65 antibody epitope patterns of patients with Type 1.5 differ from that of Type 1 diabetes patients. Diabetes Care 2002;25:1481–1482.

    Google Scholar 

  41. Hampe CS, Hammerle LP, Örtqvist E, Kockum I, Rolandsson O, Landin-Olsson M, Törn C, Persson B, Lernmark Å. Recognition of glutamic acid decarboxylase (GAD) by autoantibodies from different GAD antibody-positive phenotypes. J Clin Endo Metab 2000;85:4671–4679.

    Google Scholar 

  42. Kobayashi T, Tanaka S, Okubo M, Nakanishi K, Murase T, Lernmark Å. Unique epitopes of glutamic acid decarboxylase autoantibodies in slowly proressive and acute-onset type 1 diabetes (manuscript submitted).

  43. Brooks-Worrell BM, Juneja R, Minokadeh A, Greenbaum CJ, Palmer JP. Cellular immune responses to human islet proteins in antibody-positive type 2 diabetic patients. Diabetes 1999;48:983– 988.

    Google Scholar 

  44. Zimmet P. Antibodies to glutamic acid decarboxylase in the prediction of insulin dependency. Diab Res Clin Pract 1996;34:S125–S131.

    Google Scholar 

  45. Willis JA, Scott RS, Brown LJ, Forbes LV, Schmidli RS, Zimmet PZ, MacKay IR, Rowley MJ. Islet cell antibodies and antibodies against glutamic acid decarboxylase in newly diagnosed adult-onset diabetes mellitus. Diab Res Clin Pract 1996;33:89–97.

    Google Scholar 

  46. Fukui M, Nakano K, Shigeta H, Yoshimori K, Fujii M, Kitagawa Y, Mori H, Kajiyama S, Nakamura N, Abe N, Obayashi H, Fukui I, Ohta K, Ohta M, Kondo M. Antibodies to glutamic acid decarboxylase in Japanese diabetic patients with secondary failure of oral hypoglycaemic therapy. Diabet Med 1997;14:148–152.

    Google Scholar 

  47. Kasuga A, Maruyama T, Ozawa Y, Takei I, Falorni A, Lernmark A, Saruta T. Antibody to the Mr 65,000 isoform of glutamic acid decarboxylase are detected in non-insulin-dependent diabetes in Japanese. J Autoimmun 1996;9:105–111.

    Google Scholar 

  48. Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay I, Shattock M, Bottazzo GF, Holman R, UKPDS 25. Autoantibodies to islet-cell cytoplasma and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. Lancet 1997;350:1288–1293.

    Google Scholar 

  49. Falorni A, Ackefors R, Carlberg C, Daniels T, Persson B, Robertson J, Lernmark A. Diagnostic sensitivity of immunodominant epitopes of glutamic acid decarboxylase (GAD65) autoantibodies in childhood IDDM. Diabetologia 1996;39:1091–1098.

    Google Scholar 

  50. Falorni A, Gambelunghe G, Forini F, Kassi G, Cosentino A, Candeloro P, Bolli GB, Brunetti P, Calcinaro F. Autoantibody recognition of COOH-terminal epitopes of GAD65 marks the risk for insulin requirement in adult-onset diabetes mellitus. J Clin Endocrinol Metab 2000;85:309–316.

    Google Scholar 

  51. Oka Y, Katagiri H, Ishihara H, Asano T, Kobayashi T, Kikuchi M. β-cell loss and glucose induced signalling defects in diabetes mellitus caused by mitochondrial tRNA(Leu)(Uur) gene mutation. Diabet Med 1996;13:S98–S102.

    Google Scholar 

  52. Kobayashi T, Oka Y, Katagiri H, Falorni A, Kasuga A, Takei I, Nakanishi K, Murase T, Kosaka K, Lernmark A. Association between HLA and islet cell antibodies in diabetic patients with a mitochondrial DNA mutation at base pair 3243. Diabetologia 1996;39:1196–1200.

    Google Scholar 

  53. Mustonen A, Ilonen J, Tiilikainen A, Kataja M, Akerblom HK. An analysis of epidemiological data in HLA-typed diabetic children. Diabetologia 1985;28:397–400.

    Google Scholar 

  54. Vandewalle CL, Decraene T, Schuit FC, DeLeeuw IH, Pipeleers DG, Gorus FK. Insulin autoantibodies and high titre islet cell antibodies are preferentially associated with theHLADQA1*0301-DQB10302 haplotype at clinical type 1 (insulin-dependent) diabetes mellitus before age 10 years, but not at onset between age 10 and 40 years: The Belgian Diabetes Registry. Diabetologia 1993;36:1155–1162.

    Google Scholar 

  55. Lohmann T, Sessler J, Verlohren HJ, Schröder S, Rötger J, Dahn K, Morgenthaler N, Scherbaum WA. Distinct genetic and immunological features in patients with onset of IDDM before and after age 40. Diabetes Care 1997;20:524–529.

    Google Scholar 

  56. Tuomi T, Carlsson A, Li H, Isomaa B, Miettinen A, Nilsson A, Nissén M, Ehrnström BO, Forsén B, Snickars B, Lahti K, Forsblom C, Sarolanta C, Taskinen MR, Groop LC. Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 1999;48:150–157.

    Google Scholar 

  57. Hosszúfalusi N, Vatay A, Rajczy K, Prohászka Z, Pozsonyi E, Horváth L, Grosz A, Gerõ L, Madácsy L, Romics L, Karádi I, Füst G, Pánczél P: Similar genetic features and different islet cell autoantibody pattern of Latent Autoimmune Diabetes in Adults (LADA) compared with adult-onset type 1 diabetes with rapid progression. Diabetes Care 2003;26:452–457.

    Google Scholar 

  58. Horton V, Stratton I, Bottazzo GF, Shattock M, Mackay I, Zimmet P, Manley S, Holman R, Turner R. Genetic heterogeneity of autoimmune diabetes: Age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43). Diabetologia 1999;42:608–616.

    Google Scholar 

  59. Marner B, Agner T, Binder C, Lernmark A, Nerup J, Mandrup-Poulsen T, Walldorff S. Increased reduction in fasting C-peptide is associated with islet cell antibodies in type 1 (insulin-dependent) diabetic patients. Diabetologia 1985;28:875–880.

    Google Scholar 

  60. Christie M, Delovitch TL. Persistence of antibodies to a 64,000-Mr islet cell protein after onset of type I diabetes. Diabetes 1990;39:653–659.

    Google Scholar 

  61. Tarn AC, Thomas JM, Dean BM, Ingram D, Scheartz G, Botazzo GF. Predicting insulin-dependent diabetes. Lancet 1988;i:845–850.

    Google Scholar 

  62. Carlsson A, Sundkvist G, Groop L, Tuomi T. Insulin and glucagon secretion in patients with slowly progressive autoimmune diabetes (LADA). J Clin Endocrinol Metab 2000;85:76–80.

    Google Scholar 

  63. Raz I, Elias D, Avron A, Tamir M, Metzger M, Cohen IR. B-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): A randomized, double blind, phase II trial. Lancet 2001;358:1749–1753.

    Google Scholar 

  64. Gotfredsen CF, Buschard K, Frandsen EK. Reduction of diabetes incidence of BB Wistar rats by early prophylactic insulin treatment of diabetes-prone animals. Diabetologia 1985;28:933–935.

    Google Scholar 

  65. Bertrand S, De Paepe M, Vigeant C, Yale JF. Prevention of adoptive transfer in BB rats by prophylactic insulin treatment. Diabetes 1992;41:1273–1277.

    Google Scholar 

  66. Gottlieb PA, Handler ES, Appel MC, Greiner DL, Mordes JP, Rossini AA. Insulin treatment prevents diabetes mellitus but not thyroiditis in RT6-depleted diabetes resistant BB/Wor rats. Diabetologia 1991;34:296–300.

    Google Scholar 

  67. Atkinson MA, Maclaren NK, Luchetta R. Insulitis and diabetes in NOD mice reduced by prophylactic insulin therapy. Diabetes 1990;39:933–937.

    Google Scholar 

  68. Thivolet CH, Goillot E, Bedossa P, Durand A, Bonnard M, Orgiazzi J. Insulin prevents adoptive cell transfer of diabetes in the autoimmune non-obese diabetic mouse. Diabetologia 1991;34:314– 319.

    Google Scholar 

  69. Muir A, Peck A, Clare Salzler M, Song YH, Cornelius J, Luchetta R, Krischer J, Maclaren N. Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-gamma transcription. J Clin Invest 1995;95:628– 634.

    Google Scholar 

  70. Shah SC, Malone JI, Simpson NE. A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 1989;320:550–554.

    Google Scholar 

  71. DCCT Research Group. Effects of age, duration and treatment of insulin-dependent diabetes mellitus on residual beta-cell function: Observations during eligibility testing for the Diabetes Control and Complications Trial (DCCT). J Clin Endocrinol Metab 1987;65:30– 36.

    Google Scholar 

  72. The Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. Ann Intern Med 1998;128:517–523.

    Google Scholar 

  73. Kobayashi T, Nakanishi K, Murase T, Kosaka K. Small doses of subcutaneous insulin as a strategy for preventing slowly progressive β-cell failure in islet cell antibody-positive patients with clinical features of NIDDM. Diabetes 1996;45:622–626.

    Google Scholar 

  74. Kobayashi T. Multicenter prevention trial of slowly progressive IDDMwith small dose of insulin (the Tokyo Study). Diabetes Metab Res Rev 2001;17(suppl. 1):S29-(Abstr.).

    Google Scholar 

  75. Kobayashi T, Maruyama T, Shimada A, Kasuga A, Kanatsuka A, Takei I, Tanaka S, Yokoyama J. Insulin intervention to preserve beta cells in slowly progressive insulin-dependent (type 1) diabetes mellitus. Ann NY Acad Sci 2002;958:117–130.

    Google Scholar 

  76. Diabetes Prevention Trial–Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002;346:1685–1691.

    Google Scholar 

  77. Keller RJ, Eisenbarth GS, Jackson RA. Insulin prophylaxis in individuals at high risk of type 1 diabetes. Lancet 1993;341:927– 928.

    Google Scholar 

  78. Ryu S, Kodama S, Ryu K, Schoenfeld DA, Faustman DL. Reversal of established autoimmune diabetes by restoration of endogenous β cell function. J Clin Invest 2001;108:63–72.

    Google Scholar 

  79. Palmer JP. Immunomodulatory therapy of human type 1 diabetes: Lessons from the mouse. J Clin Invest 2001;108:31–33.

    Google Scholar 

  80. Brooks-Worrell B, Gersuk VH, Greenbaum C, Palmer JP. Intermolecular antigen spreading occurs during the pre-clinical period of human type 1 diabetes. J Immunol 2001;166:5265–5270.

    Google Scholar 

  81. Shapiro AMJ, Lakey JRT, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230–238.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Naik, R.G., Palmer, J.P. Latent Autoimmune Diabetes in Adults (LADA). Rev Endocr Metab Disord 4, 233–241 (2003). https://doi.org/10.1023/A:1025148211587

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1025148211587

Navigation